The androgen receptor (AR) is a member of the steroid nuclear-receptor superfamily of ligand-dependent transcription factors. The binding of androgen to AR initiates the gene activation required for male sex development.
AR is an important target primarily in two drug discovery areas. In oncology drug discovery, inhibitors (antagonists or partial antagonists) of androgen receptor function are useful for treatment of anti-androgen refractory prostate cancer. In metabolic diseases drug discovery, agonists or partial agonists to the androgen receptor in muscle are useful to treat age-related diseases.
As with the other members of the steroid receptor family, AR has several functional domains including a DNA binding domain (DBD), and a 261 residue ligand-binding domain (LBD) (Mw=30,245 Da) which contains the androgen binding site, and is responsible for switching on the androgen function.
Development of synthetic ligands that specifically bind to androgen receptors has been largely guided by trial and error method of drug design despite the importance of the androgen receptor in physiological processes and medical conditions such as prostate cancer and modulation of reproductive organ modulation. Previously, new ligands specific for androgen receptors were discovered in the absence of information on the three dimensional structure of the androgen receptor with a bound ligand. Before the present invention, researchers were essentially discovering androgen receptor ligands by probing in the dark and without the ability to visualize how the amino acids of the androgen receptor held a ligand in its grasp.
Consequently, it would be advantageous to devise methods and compositions for reducing the time required to discover ligands to the androgen receptor, synthesize such compounds and administer such compounds to organisms to modulate physiological processes regulated by the androgen receptor.
The cDNA and amino acid sequences of human and rat androgen receptors have been described (Proc. Natl. Acad. Sci. U.S.A. 1988 85: 7211–7215). However, there have been no crystals reported of any androgen receptor. Thus, x-ray crystallographic analysis of such proteins has not been possible.
We have discovered the first crystal structure of the androgen receptor ligand binding domain (AR-LBD). Our understanding of the androgen receptor structure has allowed for the determination of the ligand binding site for selective androgen receptor modulators (SARMs).